More than half of individuals treated for HIV-infection now demonstrate changes in body fat distribution, including increased visceral adiposity and peripheral fat atrophy. Along with these changes, HIV-infected patients are at increased risk for insulin resistance, diabetes, dyslipidemia, and cardiovascular disease. This grant proposal investigates a novel strategy to decrease abdominal fat and reduce metabolic risk in HIV- infection by augmenting endogenous growth hormone (GH) secretion through the use of growth hormone releasing hormone (GHRH1-44). The rationale for this strategy stems from data that HIV-infected patients with abdominal fat accumulation are relatively GH deficient, and from clinical observations that GH replacement in other populations with GH deficiency improves body composition and ameliorates cardiometabolic risk. The use of GHRH1-44 in this application, in contrast to the use of exogenous recombinant human GH (rhGH), is proposed in order to augment physiologic pituitary GH secretion rather than providing apulsatile exogenous replacement. Our preliminary data demonstrate that GHRH1-44 increases endogenous pulsatile growth hormone secretion, which we hypothesize will lead to greater efficacy and reduced side effects as compared to exogenous rhGH. Previous studies have demonstrated that GHRH1-44 reduces visceral fat accumulation and improves dyslipidemia. In this proposal we hypothesize that GHRH1-44 will also decrease ectopic fat in liver and muscle, potentially ameliorating insulin resistance. Two studies are proposed in this application - a short-term comparison of the effects of GHRH1-44 vs. rhGH on endogenous GH pulsatility and insulin sensitivity, and a 1 year randomized placebo-controlled trial measuring the effects of GHRH1-44 on lipolysis, insulin sensitivity, and ectopic fat accumulation. Together, data from these studies will characterize the metabolic effects GHRH1- 44 and, additionally, will explore the physiologic importance of GH pulsatility by contrasting the effects of GHRH1-44 vs. rhGH. With these goals, the proposed research will both enhance our understanding of GH physiology and contribute to the development of a potentially important new treatment strategy for metabolic complications of HIV. The candidate in this application, Dr. Takara Stanley, is a pediatric endocrinologist with clinical research experience in metabolic and endocrine complications of HIV-infection. Dr. Stanley's career goal is to perform patient-oriented research in an academic setting, focusing on the metabolic and endocrine aspects of body fat distribution. In the current proposal, Dr. Stanley will explore these themes through the model of HIV-lipodystrophy. As she progresses in her career, she plans to expand her field of investigation to pediatric conditions of abdominal obesity. The proposed studies will provide Dr. Stanley with experience and training in numerous methods of physiologic investigation, including techniques for analyzing hormone secretory dynamics, glucose homeostasis, and lipid metabolism. In addition, the proposed career development plan will provide Dr. Stanley will further training in statistics and drug development. The mentor in this proposal, Dr. Steven Grinspoon, is an internationally recognized expert in the field of HIV-associated endocrine and metabolic complications. In addition to being a well-established and well-funded clinical researcher, he is an accomplished mentor with the skills and infrastructure necessary to mentor Dr. Stanley and help her transition to independence. Along with the mentorship of Dr. Grinspoon, the career development plan proposed in this application will provide Dr. Stanley with the training and skills to become an independent clinical investigator. PUBLIC HEALTH RELEVANCE: This project will determine the metabolic effects of a new therapy, growth hormone releasing hormone (GHRH1-44), to reduce abdominal fat and improve metabolism in patients with HIV-infection and increased belly size. The research will contribute to our knowledge of this important potential therapy for complications of HIV-infection, and will also increase our understanding of how growth hormone affects sugar and fat metabolism.